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NEW DRUG APPLICATION
DRUG APPROVAL PROCESS
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A Regulatory process by which a
person/organization/sponsor/innovator gets
authorization to launch a new drug in the market is
known as drug approval process
NEW DRUG APPROVAL:
A submission to the USFDA or concerned
regulatory authority of the country containing
clinical and non-clinical teat data/analysis reports
along with drug chemistry information
INTRODUCTION
The FDA has established guidelines for formatting,
assembling & submitting the NDA
 Failure to follow these guidelines can result in
deficiencies that could
▪Delay review
▪Require an amended application
▪Result in a refusal to file
• NDA shares most common elements with the CTD
developed by the ICH
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INTRODUCTION
The new drug application(NDA) is a critical
component in the drug approval process
 The NDA contains
 Clinical and non-clinical test data and analyses
 Drug chemistry information
 Descriptions of manufacturing procedures
 An NDA consists of thousands of pages of
information to be reviewed by FDA teams composed
of highly qualified individuals with expertise in their
respective technical fields
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INTRODUCTION
Usually six different teams are responsible for
reviewing an NDA
 The teams are organized by technical reviewing
responsibilities
▪Clinical
▪Pharmacology/Toxicology
▪Chemistry
▪Statistics
▪Biopharmaceutical &
▪Microbiology
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NDA GOALS
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The goals of the NDA are to provide enough information
to permit FDA reviewers to establish the following:
Is the drug safe and effective in its proposed use(s)
when used as directed, and do the benefits of the drug
outweigh the risks?
Is the drug’s proposed labeling (package insert)
appropriate, and what should it contain?
Are the methods used in manufacturing (Good
Manufacturing Practice, GMP) the drug and the controls
used to maintain the drug’s quality adequate to
preserve the drug’s identity, strength, quality, and
purity?
NDA COPIES
FDA requires drug sponsors to submit multiple copies of the
NDA
1 ARCHIVAL COPY:
◊ The cover letter,
◊The administrative section
◊It must contain four copies of labeling section
◊It must contain three additional copies of CMC and
methods validation package in a separate binder
◊Only copy that contains the case report tabulation and
case report forms
NDA COPIES
2 REVIEW COPY:
It contains the NDA’s technical
sections along with the cover letter, form
FDA-356 h, NDA index as well as individual
table of content, the labeling section and
application summary
3FIELD COPY:
Its required by FDA inspectors during preapproval facilities inspection. In addition to
content of review copy includes CMC and
methods validation package
NDA CONTENTS
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NDA Section 1: Index
NDA Section 2: labeling
NDA Section3: application summary
NDA Section 4: Chemistry , Manufacturing, controls (CMC)
NDA Section 5: Non-clinical pharmacology and Toxicology
NDA Section 6: Human pharmacokinetics and Bioavailability
NDA Section 7: Microbiology
NDA Section 8: clinical data
NDA Section 9: Safety Update Reports
NDA CONTENTS
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NDA Section 10: Statistics
NDA Section 11: Case Report Form Tabulations
NDA Section 12: Case Report Forms
NDA Section 13: Patent Information
NDA Section 14: Patent Certification
NDA Section 15: Establishment Description
NDA Section 16: Debarment Certificate
NDA Section 17: Field Copy Certification
NDA Section 18: User Fee Coversheet
NDA Section 19: Financial Disclosure
NDA Section 20: others
BEFORE TRIALS
To legally test the drug on human subjects in the
U.S., the maker must first obtain an Investigational
New Drug (IND) designation from FDA. This
application is based on pre-clinical data, typically
from animal studies after P1, that shows the drug
is safe enough to be tested in humans.
 Often the "new" drugs that are submitted for
approval include new molecular entities or old
medications that have been chemically modified
to elicit differential pharmacological effects or
reduced side-effects.
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CLINICAL TRIALS
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The legal requirement for approval is "substantial"
evidence of efficacy demonstrated through controlled
clinical trials.
This standard lies at the heart of the regulatory program
for drugs.
It means that the clinical experience of doctors, the
opinion of experts, or testimonials from patients, even if
they have experienced a miraculous recovery, have
minimal weight in this process.
Data for the submission must come from rigorous
clinical trials
CLINICAL TRIALS
The trials are typically conducted in three phases:
 PHASE 1: The drug is tested in a few healthy volunteers to
determine if it is acutely toxic.
 PHASE 2: Various doses of the drug are tried to determine
how much to give to patients.
 PHASE 3: The drug is typically tested in double-blind, placebo
controlled trials to demonstrate that it works. Sponsors
typically confer with FDA prior to starting these trials to
determine what data is needed, since these trials often
involve hundreds of patients and are very expensive.
 (PHASE 4): These are post-approval trials that are
sometimes a condition attached by the FDA to the approval.
CLINICAL TRIALS
If the FDA gives the green light, the "investigative"
drug will then enter three phases of clinical trials:
 PHASE 1: uses 20-80 healthy volunteers to
establish a drug's safety and profile. (about 1
year)
 PHASE 2: employs 100-300 patient volunteers to
assess the drug's effectiveness. (about 2 years)
 PHASE 3: involves 1000-3000 patients in clinics
and hospitals who are monitored carefully to
determine effectiveness and identify adverse
reactions. (about 3 years)
THE ACTUAL APPLICATION
The results of the testing program are codified in
an FDA-approved public document that is called
the product label, package insert or Full
Prescribing Information.
 The prescribing information is widely available on
the web, from the FDA, drug manufacturers, and
frequently inserted into drug packages.
 The main purpose of a drug label is to provide
healthcare providers with adequate information
and directions for the safe use of the drug
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THE ACTUAL APPLICATION
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The documentation required in an NDA is supposed to
tell the drug’s whole story, including what happened
during the clinical tests, what the ingredients of the drug
formulation are, the results of the animal studies, how
the drug behaves in the body, and how it is
manufactured, processed and packaged.
Currently, the decision process for FDA approval lacks
transparency; however, efforts are underway to
standardize the benefit-risk assessment of new
medicines. Once approval of an NDA is obtained, the
new drug can be legally marketed starting that day in
the U.S.
THE ACTUAL APPLICATION
Once the application is submitted, the FDA has 60 days to
conduct a preliminary review which will assess whether
the NDA is "sufficiently complete to permit a substantive
review".
If the NDA is found to be insufficiently complete (and
reasons for this can vary from a simple administrative
mistake in the application to a requirement to reconduct much of the testing).
Then the FDA rejects the application with the issue of a
Refuse to File letter which is sent to the applicant
explaining where the application has failed to meet
requirements.
THE ACTUAL APPLICATION
Assuming that everything is found to be
acceptable, the FDA will decide if the NDA will get
a standard or accelerated review and
communicate the acceptance of the application
and their review choice in another communication
known as the 74-day letter
 A standard review implies an FDA decision within
about 10 months while a priority review should
complete within 6 months.
 Of original NDAs submitted in 2009, 94 out of 131
(72%) were in eCTD format.
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THE ACTUAL APPLICATION
There is no requirement for any registration of a
drug in India. However, there is need for approval
from the Drug Controller of India (DCI) to import,
market, or manufacture a “new drug.”
 All new drugs (drugs not previously used in India
or in use for less than four years) proposed to be
introduced must be approved for import or
manufacture in India by the DCI.
 The application for permission to import or
manufacture must be accompanied by the
appropriate dossier as follows.
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THE SET OF DATA TO BE SUBMITTED
CONSISTS OF
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Introduction: description of drug and therapeutic class
Clinical and pharmaceutical information
Animal pharmacology
Animal toxicology
Human/ clinical pharmacology (Phase I)
Exploratory clinical trials (Phase II)
Confirmatory clinical trials (Phase III)
Special studies
Regulatory status in other countries
Marketing information
SET OF DATA TO BE SUBMITTED
All items above may not be required for all
drugs.
 In case the drug is already approved and
marketed abroad, then only Phase III trials may
be required in India.
 Further, such trials would need to be
conducted on at least 100 persons spread over
3-4 locations in the country
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DIFFERENT FEES CHARGED BY DRA IN
INDIA
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Application by same applicant,
for modified dosage form or with new claim
= Rs.15, 000/= Rs. 15,000/-
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Secondary applicants after 1
year of approval
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Import / Mfg FDC
= Rs. 15,000/-
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Conduct Clinical trial with ND/IND
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–Phase I
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–Phase II
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–Phase III
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= Rs. 50,000/= Rs. 25,000/= Rs. 25,000/-
DATA SUBMITTED ALONG WITH THE
APPLICATION
A. Permission to market new drug
1. Chemical and Pharmaceutical information
2. Animal Pharmacology
3. Animal Toxicology
4. Human / Clinical Pharmacology
5. Exploratory Clinical Trials
6. Confirmatory Clinical Trials
7. Bioavailability / dissolution and stability data
8 Regulatory status in other countries
9. Marketing information:
(a) Proposed product monograph
(b) Drafts of labels and cartons
10 . Application for test license :
B. SUBSEQUENT APPROVAL / PERMISSION FOR
MANUFACTURE OF ALREADY APPROVED NEW
DRUG
a) Formulation:
 Bioavailability / bioequivalence
 Name of the investigator / centre
 Source of raw material and stability
b) Raw Material
 Manufacturing Method
 QC parameters, specs, stability
 Animal toxicity
C. APPROVAL / PERMISSION FOR FDC
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Justification
PHARMACOKINETIC / Pharmacodynamic
data
 Any other data
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D. SUBSEQUENT APPROVAL OR APPROVAL FOR NEW
INDICATION – NEW DOSAGE FORM:
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Number and date of Approval already granted
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Justification
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Data on safety, efficacy and quality
APPLICATIONS FILED IN INDIA
Yes, There are applications filed by industries.
Examples are:
 Aurobindo (Zidovudine Tablets 60mg ((NDA 22294) and tentative approval for Lamivudine &
Zidovudine Tablets 30mg / 60mg ((NDA 22296))
 And Ranbaxy (oral controlled- release products
).
REFERENCES
WWW.FDA.GOV
 WWW.medicalnewstoday.com
 www.drugs.com
 www.access.gpo.gov
 www.seoho.biz
 NEW DRUG APPROVAL PROCESS by
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RICHARD.A.GUARINO
THANKU